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Beta-Amyloid 42/40 Ratio and Apolipoprotein E (ApoE) Isoform Panel, CSF

Beta-Amyloid 42/40 Ratio and Apolipoprotein E (ApoE) Isoform Panel, CSF

Test Summary

Beta-Amyloid 42/40 Ratio and Apolipoprotein E (ApoE) Isoform Panel, CSF


Clinical Use

  • Assess the likelihood of Alzheimer disease (AD) in adults with signs of mild cognitive impairment (MCI) or dementia

Clinical Background

Alzheimer disease (AD) is the most common form of dementia in the elderly. Currently, more than 5 million people in the United States have AD; the number is expected to rise to 16 million by 2050 as the population ages.1 In its early stages, dementia presents as mild cognitive impairment (MCI). This stage is characterized by a small decline in cognition noticeable to the patient, their family members, or their friends. MCI progresses to AD in about one-third of these patients.2 Assessing the risk that a person with MCI or dementia has AD can help patients and their families to better prepare for future care needs, enable eligibility for clinical trials, and, importantly, help identify potentially reversible non-AD causes.3

Intracellular deposition of amyloid in brain is an early process driving the pathophysiology of AD. Impaired clearance of beta-amyloid from the brain is reflected by decreased levels of the peptide beta-amyloid 42 (Aβ42) in cerebral spinal fluid (CSF). Consequently, low levels of Aβ42 in CSF is one of the most established biomarkers for AD pathology in dementia and MCI, and is included in diagnostic criteria by international working groups.4,5 However, the measurement of CSF Aβ42 alone has drawbacks: 1) there is a wide range of Aβ42 levels in CSF due to variations in beta-amyloid clearance between individuals; and 2) Aβ42 sticks to collection tube surfaces, leading to loss during sample testing.6

The ratio of Aβ42 to beta-amyloid 40 (Aβ40) in CSF was recently found to have better concordance with beta-amyloid deposition than Aβ42 levels alone.6,7 The ratio of Aβ42 to Aβ40 provides greater assessment accuracy because it controls for differences in total beta-amyloid between patients. In addition, because Aβ40 has similar physiochemical properties to Aβ42, the ratio also controls for loss of beta-amyloid during sample handling. In a study using 3 different immunoassays, the ratio of Aβ42 to Aβ40 in CSF had higher sensitivity (90%-97%) and specificity (88%-95%) than Aβ42 alone (sensitivity, 73%-85%; specificity 78%-89%) for amyloid deposition as measured by positron emission tomography (amyloid PET).7 Amyloid PET results demonstrate strong agreement with postmortem plaque measurements that provide a definitive AD diagnosis. In addition, use of the ratio improved differentiation of AD from non-AD dementias.7

Apolipoprotein E (ApoE), the primary brain apolipoprotein, is another CSF biomarker for AD; the ApoE concentration is lower in AD than in healthy controls.8 In addition, the APOE gene has isoforms (produced from APOE ɛ2, ɛ3 or ɛ4 gene alleles) that are associated with AD risk. The presence of an ɛ4 allele confers higher risk of AD compared with ɛ3 (the most common allele), whereas the ɛ2 allele appears to have a protective effect.9,10 Gender, environment, race, ethnicity, and presence of other risk alleles also contribute to the risk of AD associated with APOE genotype.9,10

The Beta-Amyloid 42/40 Ratio and Apolipoprotein E (ApoE) Isoform Panel, CSF, combines results for these biomarkers into an algorithm to assess the cause of MCI and the risk of AD. The biomarkers are measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). High accuracy is attained by the incorporation of isotopically labeled internal standards. Unique peptides representing Aβ42, Aβ40, and ApoE isoforms (E2, E3, and E4 corresponding to the ɛ2, ɛ3, and ɛ4 alleles, respectively), are specifically quantified based on their masses. ApoE phenotypes are identified based on the detection of isoform-specific peptide(s).

Individuals Suitable for Testing

  • Adults exhibiting signs of MCI or dementia


  • LC-MS/MS

  • Specific-peptides from digested beta-amyloid and ApoE proteins are used for quantification and to determine ApoE phenotype corresponding to the APOE genotype
  • Analytical measurement ranges:

       Aβ42: 250 – 25,000 pg/mL

       Aβ40: 250 – 25,000 pg/mL

       ApoE: 1.0 – 20.0 µg/mL

  • An algorithm incorporating the ratio of Aβ42 to Aβ40, ApoE concentration, and ApoE phenotype is used to stratify patient risk for AD as low, average, or medium
  • Results reported include:

       Aβ42 and Aβ40 concentrations, Aβ42/40 with cutoff values that define AD risk categories

       ApoE concentration and isoform (phenotype) with AD risk compared to the most common combination of ApoE isoforms (E3/E3)

       A risk assessment score calculated by the algorithm (based on all test components) with cutoff values that define AD risk categories

Panel components can be ordered separately: Abeta 42/40 Ratio (94627), ApoE Isoform (94626).

Interpretive Information

Presence of the following indicates a high risk of AD:

  • ApoE E4 isoform-specific peptide
  • Aβ42/40 <0.20
  • Risk assessment score >1.419

Presence of the following indicates a low risk of AD:

  • ApoE E2 isoform-specific peptide (in the absence of E4)
  • Aβ42/40 >0.25
  • Risk assessment score <-0.918

Presence of the following indicates an average risk of AD:

  • ApoE E3 isoform-specific peptide (in the absence of E4)
  • Aβ42/40 0.20 to 0.25
  • Risk assessment score -0.918 to 1.419

The likelihood of AD as the underlying cause for dementia or MCI should be considered in light of findings from medical and family history, physical, neurological and neuropsychological examination, and neuroimaging.



  1. Alzheimer's Association. 2017 Alzheimer's disease facts and figures. Alzheimer's & Dementia. 2017;13:325-373.

  2. Mitchell AJ, Shiri-Feshki M. Rate of progression of mild cognitive impairment to dementia—meta-analysis of 41 robust inception cohort studies. Acta Psychiatr Scand. 2009;119:252-265.

  3. Morley JE, Morris JC, Berg-Weger M, et al. Brain health: the importance of recognizing cognitive impairment: an IAGG consensus conference. J Am Med Dir Assoc. 2015;16:731-739.

  4. Herukka SK, Simonsen AH, Andreasen N, et al. Recommendations for cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic evaluation of mild cognitive impairment. Alzheimers Dement. 2017;13:285-295.

  5. Simonsen AH, Herukka SK, Andreasen N, et al. Recommendations for CSF AD biomarkers in the diagnostic evaluation of dementia. Alzheimers Dement. 2017;13:274-284.

  6. Lewczuk P, Matzen A, Blennow K, et al. Cerebrospinal fluid Abeta42/40 corresponds better than Abeta42 to amyloid PET in Alzheimer's disease. J Alzheimers Dis. 2017;55:813-822.

  7. Janelidze S, Zetterberg H, Mattsson N, et al. CSF Abeta42/Abeta40 and Abeta42/Abeta38 ratios: better diagnostic markers of Alzheimer disease. Ann Clin Transl Neurol. 2016;3:154-165.

  8. Talwar P, Sinha J, Grover S, et al. Meta-analysis of apolipoprotein E levels in the cerebrospinal fluid of patients with Alzheimer's disease. J Neurol Sci. 2016;360:179-187.

  9. Maiti TK, Konar S, Bir S, et al. Role of apolipoprotein E polymorphism as a prognostic marker in traumatic brain injury and neurodegenerative disease: a critical review. Neurosurg Focus. 2015;39:E3. doi:10.3171/2015.8.FOCUS15329

  10. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997;278:1349-1356.

Content reviewed 06/2017

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